Apoptosis In Esophageal Cancer Cells Research Articles

HADHA promotes esophageal cancer progression by activating mTOR signaling and the SP1/MDM2 axis.

Esophageal cancer (EC) is one of the most recalcitrant cancers, with a 5-year survival rate of <30%. The hydroxyacyl-CoA dehydrogenase alpha subunit (HADHA) plays an essential role in long-chain fatty acid metabolism, and dysregulation of HADHA has been demonstrated to be involved in a series of metabolic diseases and cancers. However, its role in cancers remains controversial. HADHA has seldom been investigated in EC, and little is known about how HADHA regulates the malignant progression of EC. In this study, we find that HADHA is significantly upregulated in EC tissues and is correlated with poor survival. HADHA knockdown markedly inhibits EC cell proliferation both in vitro and in vivo. The loss of HADHA also induces EC cell apoptosis, causes cell cycle arrest and inhibits cell migration. Additionally, RNA profiling reveals that mTOR signaling is significantly suppressed after HADHA knockdown. Mechanistically, HADHA interacts with SP1 and induces MDM2 expression. In conclusion, both mTOR signaling and the SP1-MDM2 axis participate in the HADHA-induced malignant behavior of EC cells.

FOXP4-AS1 promotes CD8+ T cell exhaustion and esophageal cancer immune escape through USP10-stabilized PD-L1.

Esophageal cancer (EC) is the 9th most frequently diagnosed malignancy globally with unfavorable prognosis. Immune escape is one of the principal factors leading to poor survival, however, the mechanism underlying immune escape remains largely uninvestigated. The xenograft mouse model and EC cell-CD8+ cytotoxic T lymphocytes (CTLs) co-culture system were established. Immunohistochemistry, qRT-PCR or western blot were employed to detect the levels of long non-coding RNA (lncRNA) FOXP4-AS1, PD-L1, USP10 and other molecules. The abundance of T cells, cytokine production and cell apoptosis were monitored by flow cytometry. The viability of CTLs was assessed by Trypan blue staining. The binding between FOXP4-AS1 and USP10 was validated by RNA pull-down assay, and the interaction between USP10 and PD-L1, as well as the ubiquitination of PD-L1, were detected by co-immunoprecipitation. The elevation of FOXP4-AS1 in EC was associated with decreased CTL abundance, and upregulated PD-L1 facilitated CTL apoptosis in EC. FOXP4-AS1 accelerated EC tumor growth by decreasing the abundance of tumor infiltrating CTLs in vivo. FOXP4-AS1 inhibited the viability of CTLs and facilitated the cytotoxicity and exhaustion of CTLs. In Kyse 450 cell-CTL co-culture system, FOXP4-AS1 suppressed the viability and abundance of CTLs, and inhibited EC cell apoptosis via PD-L1. Mechanistically, FOXP4-AS1 regulated the ubiquitination of PD-L1 through deubiquitinating enzyme USP10. FOXP4-AS1 promoted CTL exhaustion and EC immune escape through USP10-stabilized PD-L1. HIGHLIGHTS: PD-L1 facilitated CD8+ T cell apoptosis in EC. Upregulated FOXP4-AS1 promoted EC tumor growth by inhibiting the viability and facilitating the cytotoxicity and exhaustion of tumor infiltrating CD8+ T cells. FOXP4-AS1 suppressed the viability and abundance of CD8+ T cells through USP10-mediated deubiquitination of PD-L1.

Discovery of TK-642 as a highly potent, selective, orally bioavailable pyrazolopyrazine-based allosteric SHP2 inhibitor

Src homology-2-containing protein tyrosine phosphatase 2 (SHP2) is a promising therapeutic target for cancer therapy. In this work, we presented the structure-guided design of 5,6-fused bicyclic allosteric SHP2 inhibitors, leading to the identification of pyrazolopyrazine-based TK-642 as a highly potent, selective, orally bioavailable allosteric SHP2 inhibitor (SHP2WT IC50 = 2.7 nmol/L) with favorable pharmacokinetic profiles (F = 42.5%; t1/2 = 2.47 h). Both dual inhibition biochemical assay and docking analysis indicated that TK-642 likely bound to the “tunnel” allosteric site of SHP2. TK-642 could effectively suppress cell proliferation (KYSE-520 cells IC50 = 5.73 μmol/L) and induce apoptosis in esophageal cancer cells by targeting the SHP2-mediated AKT and ERK signaling pathways. Additionally, oral administration of TK-642 also demonstrated effective anti-tumor effects in the KYSE-520 xenograft mouse model, with a T/C value of 83.69%. Collectively, TK-642 may warrant further investigation as a promising lead compound for the treatment of esophageal cancer.

The antagonistic effect of FTO on METTL14 promotes AKT3 m6A demethylation and the progression of esophageal cancer

BackgroundAs the most abundant modification in eukaryotic messenger RNAs (mRNAs), N6-methyladenosine (m6A) plays vital roles in many biological processes.MethodsMethylated RNA immunoprecipitation sequencing (MeRIP-seq) and transcriptomic RNA sequencing (RNA-seq) were used to screen for m6A targets in esophageal cancer cells and patients. The role of m6A RNA methylase in esophageal cancer was also analyzed using bioinformatics. In vitro and in vivo experiments were used to analyze gene expression and function. CCK-8, colony formation, cell apoptosis and immunofluorescence staining assays were performed to evaluate the proliferation, migration and invasion of esophageal cancer cells, respectively. Western blot analysis, RNA stability, RIP and luciferase reporter assays were performed to elucidate the underlying mechanism involved.ResultsWe found that the m6A demethylase FTO was significantly upregulated in esophageal cancer cell lines and patient tissues. In vivo and in vitro assays demonstrated that FTO was involved in the proliferation and apoptosis of esophageal cancer cells. Moreover, we found that the m6A methyltransferase METTL14 negatively regulates FTO function in esophageal cancer progression. FTO alone is not related to the prognosis of esophageal cancer, and its function is antagonized by METTL14. By using transcriptome-wide m6A-seq and RNA-seq assays, we revealed that AKT3 is a downstream target of FTO and acts in concert to regulate the tumorigenesis and metastasis of esophageal cancer. Taken together, these findings provide insight into m6A-mediated tumorigenesis in esophageal cancer and could lead to the design of new therapeutic strategies.

Hsa_circ_0001615 downregulation inhibits esophageal cancer development through miR-142-5p/β-catenin.

Recent studies have found that circular RNAs (circRNAs) play important roles in tumorigenesis. This study aimed to determine the function and potential mechanisms of hsa_circ_0001615 in esophageal cancer. Quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) was used to validate the expression of hsa_circ_0001615 and miR-142-5p. Subsequently, 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium salt, flow cytometry, clone formation, and transwell assays were used to assess the function of hsa_circ_0001615. Furthermore, qRT-PCR and Western blot analysis were used to verify cyclin D1, Bcl-2 associated X, B-cell lymphoma/leukemia gene-2, and β-catenin levels. Circular RNA Interactome was used to estimate the binding site between hsa_circ_0001615 and miR-142-5p. Additionally, dual-luciferase reporter assays were used to determine whether miR-142-5p was a direct target of hsa_circ_0001615. Pearson correlation analysis was used to explore the relationship between miR-142-5p and hsa_circ_0001615. In esophageal cancer, the expressions of hsa_circ_0001615 and miR-142-5p were increased and decreased, respectively. Hsa_circ_0001615 inhibition significantly reduced the proliferation, migration, and invasion but increased the apoptosis of esophageal cancer cells. Additionally, hsa_circ_0001615 knockdown increased miR-142-5p expression but decreased β-catenin expression. MiR-142-5p was a direct target of hsa_circ_0001615. Hsa_circ_0001615 knockdown could mediate antitumor effects through the miR-142-5p/β-catenin pathway.

Cysteine protease inhibitor S promotes lymph node metastasis of esophageal cancer cells via VEGF-MAPK/ERK-MMP9/2 pathway.

Cysteine protease inhibitor S (CST4) plays a pivotal role in the regulation of growth, invasion, and metastasis of a variety of malignancies. However, the potential mechanism behind how CST4 contributes to CST4 in lymph node metastasis (LNM) and tumor-associated lymphangiogenesis of esophageal cancer (EC) cells has not been elucidated previously. Short hairpin RNA technique was utilized to upregulate the CST4 gene expression. Different experiments, including the tubule formation assay and immunofluorescence, were conducted to observe the cellular behavior. Enzyme-linked immunosorbent assay (ELISA) and Western blot analyses were employed to determine the expression levels of relevant proteins. In our study, we discovered that high expression of CST4 in EC cells had multiple effects. It stimulated cell proliferation, invasion, and migration and caused epithelial-mesenchymal transition (EMT). Moreover, it also inhibited the apoptosis of EC cells and caused them to stagnate in the G2/M phase. High expression of CST4 promoted the secretion of lymphangiogenic markers (TGFβ1, VEGF, VEGF-C/D) in EC cells. In addition, high expression of CST4 in EC cells not only enhanced the proliferation and migration of HLECs, but also stimulated the lumen formation and F-actin expression and rearrangement of HLECs. The elevated expression of CST4 also facilitated the secretion of p-ERK1/2, MMP9, and MMP-2 in HLECs. However, various tumor-promoting effects of high expression of CST4 on HLECs could be inhibited by VEGF inhibitors in EC cells. Overall, our findings indicate that CST4 plays a significant role in the accumulation, migration, and EMT of EC cells. CST4 can activate the VEGF-MAPK/ERK-MMP9/2 signaling axis to promote LNM and lymphangiogenesis in EC.

Retraction: MiR-25-3p targets PTEN to regulate the migration, invasion, and apoptosis of esophageal cancer cells via the PI3K/AKT pathway.

Retraction: MiR-25-3p targets PTEN to regulate the migration, invasion, and apoptosis of esophageal cancer cells via the PI3K/AKT pathway.

Hypoxia-induced factor-1α promotes radioresistance of esophageal cancer cells by transcriptionally activating LINC01116 and suppressing miR-3612 under hypoxia.

Esophageal cancer (EC) is a challenging tumor to treat with radiotherapy, often exhibiting resistance to this treatment modality. To explore the factors influencing radioresistance, we focused on the role of hypoxia-induced factor-1α (HIF-1α), and its interaction with the long noncoding RNA long intergenic nonprotein coding RNA 1116 (LINC01116). We analyzed the LINC01116 expression in EC and EC cell lines/human normal esophageal epithelial cell line (Het-1A). LINC01116 was silenced/overexpressed in EC109/KYSE30 cells under hypoxia, followed by radioresistance assessment. We measured HIF-1α levels in hypoxic EC cells and further validated the binding of HIF-1α with LINC01116, analyzing their interaction in EC cells. We then performed experiments in EC109 cells by transfection them with sh-HIF-1α/oe-LINC01116 to verify the effects. Additonally, we analyzed the localization of LINC01116 and its binding with miR-3612, followed by a combined experiment performed to validate the results. Our findings indicated that LINC01116 was highly expressed in EC and further elevated in hypoxic EC cells. LINC01116 was expressed at a high level in EC, which was further elevated in EC cells under hypoxic conditions. Knockdown of LINC01116 triggered EC cell apoptosis, thus suppressing radioresistance. Further investigation revealed that HIF-1α transcriptionally activated LINC01116 expression under hypoxia, and silencing HIF-1α lowered EC cell radioresistance by downregulating LINC01116. Under hypoxic conditions, LINC01116 could function as a sponge for miR-3612 and inhibit its expression. This interaction between LINC01116 and miR-3612 played a crucial role in mediating radioresistance in EC cells. Briefly, under hypoxic conditions, HIF-1α facilitates radioresistance of EC cells by transcriptionally activating LINC01116 expression and downregulating miR-3612.

Paclitaxel promotes mTOR signaling-mediated apoptosis in esophageal cancer cells by targeting MUC20.

The aim of this study was to analyze the effect of paclitaxel on the apoptosis of esophageal cancer cells in relation to MUC20. RT-qPCR analysis, a CCK-8 assay, western blotting, and flow cytometry were used to analyze the anticancer effects of paclitaxel treatment or OE-MUC20 in vitro and in vivo. The in vitro results showed that paclitaxel significantly induced MUC20 upregulation and that paclitaxel treatment or OE-MUC20 significantly decreased esophageal cancer cell viability and increased mTOR signaling activation and apoptosis. In addition, PKM2, a key downstream molecule of mTOR signaling, similarly showed significant upregulation after paclitaxel treatment in cells with OE-MUC20, and its expression was attenuated after treatment with mTOR inhibitors. In a nude mouse model, tumor growth was slow in the OE-MUC20 group and accelerated after inhibition of mTOR signaling. These data suggest that MUC20 is an important target of paclitaxel in esophageal cancer and promotes apoptosis through activation of mTOR signaling.

Ferula ferulaeoides ethyl acetate extract induces apoptosis in esophageal cancer cells via mitochondrial and PI3K/Akt/Bad pathways

BackgroundFerula ferulaeoides (Steud.) Korovin is a traditional ethnopharmacological plant used for lump elimination and as a spice, especially in places like India. It has also been employed in the livestock and food industries. This investigation aimed to explore the anti-tumor mechanisms of ethyl acetate extract fractions of dried roots of Ferula ferulaeoides (FF-EtOAc) on esophageal cancer (EC) cells. Furthermore, it was hypothesized that FF-EtOAc could inhibit EC cells growths by inducing apoptosis. ResultsIn a time- and dose-dependent manner, FF-EtOAc considerably reduced the number of migrating EC cells. And FF-EtOAc also inhibited the growth of EC cells in vivo, and it is less toxic to nude mice. In terms of the FF-EtOAc anticancer mechanism, the findings revealed that FF-EtOAc inhibited EC cells growth by activating mitochondrial signaling pathways and PI3K/Akt/Bad signaling pathways. ConclusionsThrough both in vitro and in vivo experiments, FF-EtOAc significantly exhibited anti-esophageal cancer activity. The anti-EC activity of FF-EtOAc may be due to the activation of the mitochondrial apoptotic and PI3K/Akt/Bad signaling pathways.

Long noncoding RNA SNHG6 silencing sensitized esophageal cancer cells to 5-FU via EZH2/STAT pathway

Chemotherapy was the main treatment method for esophageal cancer (EC) patients. However, chemotherapy resistance due to multiple factors is a major barrier to EC treatment. For investigating how small nucleolar RNA host gene 6 (SNHG6) affected the 5-fluorouracil (5-FU) resistance in EC as well as its possible molecular mechanism. This work conducted cell viability assay, clone formation, scratch assays together with cell apoptosis for evaluating the roles of SNHG6 and enhancer of zeste homolog 2 (EZH2, the histone-lysine N-methyltransferase). Relevant molecular mechanism was identified by RT-qPCR analysis together with Western-blot (WB) assays. Our data showed that SNHG6 expression increased in EC cells. SNHG6 promotes colony formation and migration, whereas suppresses EC cell apoptosis. SNHG6 silencing markedly promoted 5-FU-mediated suppression on KYSE150 and KYSE450 cells. Additional mechanism studies showed that SNHG6 modulating STAT3 and H3K27me3 via promoting EZH2 level. Similar to the function of SNHG6, abnormal expression of EZH2 promotes the malignancy of EC and intensifies its resistance to 5-FU. In addition, overexpression of EZH2 abolished the role of SNHG6 silencing in 5-FU sensitivity in EC cells. SNHG6 overexpression promoted malignancy of EC and increased EC cell resistance to 5-FU. Besides, further molecular mechanism studies provided a novel regulatory pathways that SNHG6 knockdown promoted EC cell sensitivity to 5-FU by modulating STAT3 and H3K27me3 via promoting EZH2 expression.

A1 adenosine receptor antagonist induces cell apoptosis in KYSE-30 and YM-1 esophageal cancer cell lines.

Adenosine A1 receptor (AA1R) has been shown to have an inhibitory effect on cell growth in several cancers; however, its function in esophageal cancer is still unclear. In this study, we examined the effect of AA1R on cell growth and apoptosis in esophageal cancer cells. In this study, YM-1 and KYSE-30 esophageal cancer cell lines were cultured. AA1R gene expression was determined by quantitative Real-time Polymerase Chain Reaction (qRT-PCR). As well, the AA1R antagonist (DPCPX) effect on cell viability was evaluated by the MTT assay. Moreover, apoptosis was assessed by annexin-V and propidium iodide staining, and the caspase-3/7 activity assay kit. qRT-PCR results indicated that the AA1R was expressed in YM-1 and KYSE-30 cells. In addition, DPCPX significantly decreased cell proliferation in both cell lines. Furthermore, the A1AR antagonist induced apoptosis in KYSE-30 and YM-1 cells. After treatment of both cell lines with DPCPX, the caspase 3/7 activity was increased. Our finding indicates the AA1R antagonist induces apoptosis through caspase 3/7 activation and can be considered a potential target in esophageal cancer therapy.

CircKRT14 upregulates E2F3 by interacting with miR-1256 to act as an oncogenic factor in esophageal cancer.

A growing number of studies have focused on the regulatory role of circular RNAs (circRNAs) in a variety of cancers. The purpose of this study was to investigate the effect of circRNA Keratin 14 (circKRT14) on the progression of esophageal cancer (EC). The levels of circKRT14, miR-1256 and E2F transcription factor 3 (E2F3) were analyzed by real-time quantitative polymerase chain reaction (qRT-PCR) and western blot. The circular structure of circKRT14 was confirmed by RNase R digestion assay. Cell apoptosis, migration and invasion were detected by flow cytometry and transwell assay. The protein levels of related factors were determined by western blot. The relationship between miR-1256 and circKRT14 or E2F3 was verified by dual-luciferase reporter assay. The in vivo function of circKRT14 was studied by xenograft tumor assay. CircKRT14 was significantly increased in EC tissues and cells. CircKRT14 silencing inhibited EC cell proliferation, migration, and invasion, but promoted EC cell apoptosis in vitro. CircKRT1 acted as a sponge for miR-1256 in EC, and in-miR-1256 abolished the inhibitory effect of circKRT14 suppression on EC cell progression. E2F3 was a target of miR-1256 and functioned as an oncogene in EC cells. MiR-1256 curbed EC progression by downregulating E2F3. CircKRT14 could affect E2F3 expression by targeting miR-1256. CircKRT14 regulated EC progression in vivo through miR-1256/E2F3 axis. These results uncovered that circKRT14 up-regulated the expression of E2F3 and promoted the malignant development of EC through sponging miR-1256.

Circ_0003340 regulates the expression of ENAH to affect the development of esophageal cancer through miR-874-3p.

Esophageal cancer is a malignant tumor with a poor prognosis and high incidence. Circular RNAs (circRNAs) have been shown to be involved in the pathogenesis of cancers, including esophageal cancer. Here, we explored the precise role of circ_0003340 in esophageal cancer development. The expression levels of circ_0003340, miR-874-3p and enabled homolog (ENAH) were detected by quantitative real-time polymerase chain reaction and western blot. Subcellular localization and RNase R assays were used to characterize circ_0003340. Cell Counting Kit 8, flow cytometry, transwell assays were used to analyze cell proliferation, apoptosis, migration and invasion. The effect of circ_0003340 on tumor growth was assessed by tumor experiments in vivo. Dual-luciferase reporter assay was used to analyze the relationship between miR-874-3p and circ_0003340 or ENAH. Circ_0003340 was mainly located in the cytoplasm and was upregulated in esophageal cancer tissues and cells. Circ_0003340 knockdown inhibited cell proliferation, migration, invasion, glucose consumption, and lactate production and induced cell apoptosis in esophageal cancer cells. Moreover, circ_0003340 knockdown suppressed tumor growth in vivo. MiR-874-3p was reduced in esophageal cancer tissues and cells, and it was a molecular mediator of circ_0003340 function in esophageal cancer cells. ENAH was identified as a direct and functional target of miR-874-3p in esophageal cancer cells. The promotion effect of circ_0003340 on ENAH was ameliorated by miR-874-3p. The data demonstrated that circ_0003340 promoted the progression of esophageal cancer through miR-874-3p/ENAH axis, which might provide novel therapeutic targets for esophageal cancer intervention.

Circ_0058063 regulates the development of esophageal cancer through miR-377-3p/HOXA1 axis.

Esophageal cancer is one of the deadliest cancers. Circular RNA (CircRNA) can be used as a tumor marker. Therefore, this provides an important idea for our research. Real-time quantitative PCR (RT-qPCR) was used to analyze the expression of circ_0058063, miR-377-3p and homeobox protein Hox-A1 (HOXA1), western blot was used to analyze the protein levels of HOXA1 and cyclinD1, B cell leukemia/lymphoma 2 associated X (Bax). Cell Counting Kit-8 (CCK-8) assay, colony formation assay and wound healing assay were used to analyze cell proliferation and migration; apoptosis was analyzed by flow cytometry. Dual-luciferase reporter assays were performed to analyze the luciferase activities. Transwell assay was used to analyze the cell invasion. A glycolysis metabolism assay was used to analyze cell glycolysis ability. Xenograft models were used to validate the effect of circ_0009035 in the growth of esophageal cancer in vivo . Circ_0009035 and HOXA1 were upregulated, while miR-377 was downregulated in esophageal cancer.. Circ_0058063 targeted miR-377-3p, and HOX4 was a target of miR-377-3p. Knockdown of circ_0058063 inhibited migration, invasion and proliferation and promoted apoptosis of esophageal cancer cells. MiR-377-3p inhibition or HOXA1 overexpression could restore the effect of si-circ_0058063 on esophageal cancer cells. Knockdown of circ_0058063 repressed the growth of esophageal cancer tumors in vivo. Our study found that circ_0058063 could regulate the expression of HOXA1 by targeting miR-377-3p, thereby affecting the progress of esophageal cancer.

SERPINB2, an Early Responsive Gene to Epigallocatechin Gallate, Inhibits Migration and Promotes Apoptosis in Esophageal Cancer Cells

Esophageal cancer is a lethal disease that frequently occurs in developing countries, the incidence of which could be declined by drinking EGCG-enriched drinks or food. SERPINB2, whose complex functions and regulations are not yet fully understood, are induced by multiple inflammatory molecules and anti-tumor agents. Here, we identify 2444 EGCG-regulated genes in esophageal cancer cells, including SERPINB2. EGCG treatment recruits NF-κB at the promoter and enhancers of SERPINB2 and activates gene transcription, which is repressed by NF-κB knockdown or inhibition. Loss of SERPINB2 leads to a faster migration rate and less expression of Caspase-3 in cancer cells. Our study demonstrates that SERPINB2 is a new tumor-suppressor gene involved in cell movement and apoptosis and could be a therapeutic target for esophageal cancer.

HOXA10 enhances cell proliferation and suppresses apoptosis in esophageal cancer via activating p38/ERK signaling pathway.

Esophageal cancer (EC) is an extremely aggressive malignant tumor. Homeobox A10 (HOXA10) is highly expressed and plays an important role in a variety of tumors. However, the function of HOXA10 in EC remains unclear. In this study, HOXA10 was observed to highly express in EC tissues and cells. Interestingly, the CCK-8 assay, flow cytometry, and colony formation assay confirmed that overexpression of HOXA10 promoted proliferation and suppressed cell apoptosis in EC cells. More importantly, the western blot assay indicated that the phosphorylation levels of ERK and p38 were elevated in EC cells overexpressed HOXA10, indicating that overexpression of HOXA10 activated p38/ERK signaling pathway in EC cells. These findings concluded that HOXA10 aggravated EC progression via activating p38/ERK signaling pathway, providing a potential therapeutic target for EC.

HMGB1 induces radioresistance through PI3K/AKT/ATM pathway in esophageal squamous cell carcinoma

BackgroundTo explore the effect of HMGB1 on the radio-sensitivity of esophageal cancer cells through regulating the PI3K/Akt/ATM pathway.Methods and resultsWe observed the expression of HMGB1 and p-ATM in biopsies of esophageal cancer patients with immunohistochemical staining. Western blot and RT-qPCR were applied to detect the protein and RNA related to PI3K/Akt/ATM pathway, respectively. In addition, we inhibited the PI3K/Akt pathway with ly294002 and activated it with IGF1, then we explored the invasion, proliferation ability, and apoptosis of esophageal cancer cells in vitro by transwell, CCK8 assay, and flow cytometry respectively. In vivo, xenograft tumor model was established in nude mice to study the effect of HMGB1 on radioresistance via PI3K/AKT/ATM Signaling Pathway. The survival rate in patients with single positive/double negative expression of HMGB1 and p-ATM was significantly higher than in those with both positive expression of HMGB1 and p-ATM, the depletion of HMGB1 combined with ly294002 significantly inhibited cell proliferation and invasion ability, meanwhile, the addition of IGF1 reversed it. Meanwhile, depletion of HMGB1 and ly294002 promoted apoptosis and arrested the cancer cells in G0/G1 cell cycle with the decreased expression of Cyclin D1 and CDK4 and improved P16. We further validated these results in vivo, the application of HMGB1 silencing promoted apoptosis of xenograft tumors after radiation, especially combined with pathway inhibitor ly294002.ConclusionsEsophageal cancer patients with high expression of HMGB1 and p-ATM have a poor prognosis after chemo-radiotherapy. Down-regulation of HMGB1 may promote the radio-sensitivity of esophageal cancer cells through regulating PI3K/Akt/ATM pathway.

A novel synthetic chalcone derivative, 2,4,6-trimethoxy-4'-nitrochalcone (Ch-19), exerted anti-tumor effects through stimulating ROS accumulation and inducing apoptosis in esophageal cancer cells.

Esophageal cancer has always been associated with poor prognosis and a low five-year survival rate. Chalcone, a flavonoid family member, has shown anti-tumor property in several types of cancer. However, few studies reported the potency and mechanisms of action of synthetic Chalcone derivatives against esophageal squamous cell carcinoma. In this study, we designed and synthesized a series of novel chalcone analogs and Ch-19 was selected for its superior anti-tumor potency. Results indicated that Ch-19 shows a dose- and time-dependent anti-tumor activity in both KYSE-450 and Eca-109 esophageal cancer cells. Moreover, treatment of Ch-19 resulted in the regression of KYSE-450 tumor xenografts in nude mice. Furthermore, we investigated the potential mechanism involved in the effective anti-tumor effects of Ch-19. As a result, we observed that Ch-19 treatment promoted ROS accumulation and caused G2/M phase arrest in both Eca-109 and KYSE-450 cancer cell lines, thereby resulting in cell apoptosis. Taken together, our study provided a novel synthetic chalcone derivative as a potential anti-tumor therapeutic candidate for treating esophageal cancer.

Inhibition of APLN suppresses cell proliferation and migration and promotes cell apoptosis in esophageal cancer cells in vitro, through activating PI3K/mTOR signaling pathway.

Esophageal cancer is the sixth leading cause of cancer mortalities globally with a high incidence rate. Apelin (APLN) plays regulatory roles in different organs. However, its role in esophageal cancer remains unknown. Therefore, our study aims to explore the effect of APLN on esophageal cancer. One hundred and eighty-four (184) esophageal tumor tissues samples from patients with esophageal cancer, and 11 esophageal tissues samples from healthy volunteers were analyzed for the expression of APLN. APLN was highly expressed in the tumor of patients with esophageal cancer and esophageal cancer cells. Patients with high expressions of APLN had a lower survival rate than the ones with low to medium expressions of APLN. Human esophageal carcinoma cell lines, TE-1 and ECA-109 cells were transfected with APLN siRNA to knockdown APLN, or transfected with pcDNA-APLN to overexpress APLN. Inhibition of APLN by siRNA-APLN reduced proliferative, migrative, and invasive abilities of esophageal cancer cells and promoted cell apoptosis, which could be all restored by pcDNA-APLN. Moreover, knocking down APLN by siRNA-APLN suppressed the PI3K/mTOR signaling pathway. These findings identify that APLN inhibition might ameliorate esophageal cancer through activating the PI3K/mTOR signaling pathway, thus APLN could be a potential target for esophageal cancer.